- The goal of this proposal is to understand better the factors that regulate hair loss, which is a major social concern associated with more common male-pattern baldness as well as more rare forms of alopecia and chemotherapy. To understand hair loss and to develop new therapies to prevent this condition, it is necessary to develop better understanding of the biology of the hair follicle, a unique structure that develops and matures mainly in prenatal skin, and cycles in the post-natal skin in a complex interaction of epithelium and mesenchyme. Once developed, the follicles undergo a cycle of renewal in three phases: telogen (resting), anagen (growth), and catagen (regression). This proposal focuses on the role of the Sonic hedgehog (Shh) signaling pathway on modulation of the hair-follicle cycle after birth. Shh function is associated with a complex pathway that includes Ptc (the Shh receptor), Smo (a G-protein coupled receptor that interacts with Ptc), a variety of signaling genes that include Wnt class proteins, and transforming growth factor-b family. Based on the known upregulation of Shh expression in the anagen phase of follicle growth, and preliminary data demonstrating that transient, adenovirus (Ad) gene transfer vector-mediated Shh expression induces anagen and robust hair growth in postnatal skin, the proposed studies are based on the hypothesis that transient (less than a week), enhanced Shh activity functions as a biologic switch that induces resting follicles to enter the anagen growth phase of the follicle cycle, with consequent hair growth. Experiments are proposed to evaluate two hypotheses in postnatal skin: (1) Transient imbalance of the Shh pathway in favor of Shh activity induces hair follicles to enter the anagen phase with consequent hair growth; and (2) for Shh to induce anagen, the enhanced expression of Shh must be in keratinocytes, and for the resulting follicle cycle to be normal, the enhanced expression must be transient (days), not persistent.